Huntington's disease (HD) is the most common inherited neurodegenerative disorder and is characterized by chorea and progressive motor, psychiatric and cognitive decline (Walker, 2007). The disease is caused by a mutation in the HD gene which encodes huntingtin (Htt) (Cell(1993)26; 72(6):971-83), a ubiquitous protein with still unclear function. The HD gene contains a polymorphic CAG trinucleotide repeat that is translated as a stretch of glutamines (polyQ) in the N-terminal of the protein. Up to 35 CAG repeats are present in healthy individuals, whereas 36 or more repeats determine HD pathology. The higher the number of CAG repeats, the earlier is disease onset (Stine et al., 1993). To date there is no cure for HD, as the mechanisms underlying the disease are still poorly understood.
Neurodegeneration in HD is likely the result of a domino effect that is triggered by mutant Htt (mHtt). Expansion of the polyQ stretch endows the mutant protein with toxic properties. As a result, neurons expressing mHtt develop a broad array of cell dysfunctions, including transcriptional dysregulation, mitochondrial metabolism aberrations, and impaired cell signaling, axonal transport and synaptic activity (Imarisio et al., 2008). HD cells are also more susceptible to apoptotic stimuli than normal cells (Hickey and Chesselet, 2003). Neurons bearing the mutation are thought to be in an abnormal homeostatic state characterized by lower thresholds for the activation of cell death (Clarke et al., 2000). This may be, at least in part, the result of impaired cell signaling and overall imbalance between activation of pro-survival and apoptotic pathways. In fact, the p53 pathway, an important player in the cell response to a variety of stressors, is upregulated in HD neurons (Bae et al., 2005; Sipione et al., 2002). On the other hand, activation of the PI3K/AKT pathway, the major pro-survival pathway in neurons (Kaplan and Miller, 2000), is impaired in HD models and patients' lymphocytes (Colin et al., 2005; Humbert et al., 2002; Song et al., 2002). The mechanism behind these dysfunctions has not been identified yet, but a role for mHtt in the regulation of growth factor receptors activity and downstream signaling has been proposed (Lievens et al., 2005; Song et al., 2002).
Generation of toxic N-terminal fragments of mHtt by proteolytic cleavage of the full-length protein represents a critical step in the development of neural dysfunction and HD pathogenesis (Graham et al., 2006; Imarisio et al., 2008). Protein cleavage and toxicity may be decreased by phosphorylation of mHtt by AKT (Humbert et al., 2002; Warby et al., 2009) and other kinases (Anne et al., 2007; Luo et al., 2005; Rangone et al., 2004; Schilling et al., 2006).
Gangliosides are sialic acid-containing glycosphingolipids that are particularly enriched in the brain, where they contribute up to 10% of the neuronal lipid content (Ledeen, 1978). Together with cholesterol and sphingomyelin, gangliosides are major components of lipid rafts—membrane microdomains involved in cell signaling—and exert important cell regulatory functions (Sonnino et al., 2007). They play a major role in cell adhesion and cell-cell interaction (Hakomori Si, 2002) and mediate communication between axons and myelin in the central nervous system (CNS) (Vyas et al., 2002). They also modulate the activity of many tyrosine kinase receptors, including EGF receptor (Yoon et al., 2006), PDGF receptor (Oblinger et al., 2003), FGF receptor (Toledo et al., 2005) and neurotrophin receptors (Ferrari et al., 1995; Mocchetti, 2005).
There remains a need, therefore, for compounds, compositions, methods and/or kits for treating and/or diagnosing neurodegenerative, and for example Huntington's disease.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.